Editors' ChoiceTuberculosis

Ctrl-Alt-Del: Host-Targeting Anti-Angiogenic Agents as Adjunct Therapy for Tuberculosis

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Science Translational Medicine  24 Dec 2014:
Vol. 6, Issue 268, pp. 268ec218
DOI: 10.1126/scitranslmed.aaa3463

Zebrafish offer an excellent model system to study various biological phenomena because of their small size, human-like developmental pattern, and optical transparency. These parallels can be extended to mycobacterial infection, which is caused by Mycobacterium tuberculosis in humans and Mycobacterium marinum in fish. Fish tuberculosis (TB) mimics many aspects of human TB infection, including granuloma formation. Granulomas, which trap infecting mycobacteria, consist of an organized collection of macrophages with a hypoxic core. In tumors, hypoxic tissue is associated with angiogenesis, but angiogenesis in the context of TB granulomas has remained unexplored.

Oehlers et al. harness the zebrafish TB model to examine angiogenesis in the context of mycobacterial infection induced granulomas. Long-term live imaging of infected zebrafish larvae clearly showed the growth of vasculature around sites of infection just after formation of granulomas at around four days post-infection. Interestingly, this angiogenic process was only triggered with live mycobacteria—not dead cells or a nonpathogenic E. coli strain. The authors then established that inhibition of signaling pathways that activate angiogenesis led to suppression of granuloma-associated angiogenesis. Indeed, the angiogensis inhibitor pazopanib greatly reduced mycobacterial burden in infected adult zebrafish in a manner complementary to the first-line anti-TB drug rifampicin.

The current study strongly underlines that targeting granuloma-associated angiogenesis may be a viable host-targeted therapeutic approach to clear Mtb infection. This adjunct therapy could be another weapon in our arsenal against drug-resistant tuberculosis.

S. H. Oehlers et al., Interception of host angiogenic signalling limits mycobacterial growth. Nature 10.1038/nature13967 (2014). [Full Text]

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